The Womens Health Initiative (WHI) randomized, placebo-controlled clinical trials of hormone therapy (HT) were designed to test the hypothesis that conjugated equine estrogens alone (CEE-Alone) or in combination with medroxyprogesterone acetate (CEE+MPA) protected postmenopausal women against the development of heart disease. The WHI Memory Study (WHIMS)was an ancillary study to the WHI trials, which consisted of parallel placebo-controlled randomized clinical trials of 0.625 mg/day CEE therapy with and without 2.5 mg/day MPA in women with a uterus or post-hysterectomy, respectively. WHIMS investigated the effect of CEE-Alone and CEE+MPA on risk for probable dementia and mild cognitive impairment in women age 65 and older, as well as the effects of these treatments on global cognitive function. WHIMS followed 7479 women at 38 of the 40 WHI clinical sites participating in the HT trial. The WHI Study of Cognitive Aging (WHISCA), an ancillary study to WHIMS, was developed to investigate the effects of HT on domain-specific cognitive function in women without dementia. Based on observational studies from our group and others and randomized trials of younger women following surgical menopause, we hypothesized that hormone therapy (HT) in postmenopausal women would benefit memory and possibly other cognitive functions. WHISCA enrolled 2305 women at 14 of the WHIMS sites, distributed across the two parallel trials. WHISCA was initiated on average 3 years after WHI randomization and the primary outcome was the effect of HT on rates of cognitive change, adjusted for time since randomization. Through the main WHI study and WHIMS, incident diagnoses of stroke, probable dementia, and mild cognitive impairment (MCI) are available for WHISCA participants. The WHIMS CEE+MPA trial terminated earlier than planned (July, 2002) due to an adverse risk-to-benefit profile in the main WHI trial. Subsequently, the WHI CEE-Alone Trial also was terminated early (February, 2004). Results from the WHIMS trials showed that CEE-Alone or CEE+MPA increase the risk of dementia and have adverse effects on global cognition in women aged 65 years or older. HT also has been shown to increase the risk of clinical stroke in women 65 years and older. The initial report of WHISCA findings (Resnick et al., Journal of Clinical Endocrinology and Metabolism, 2006) included 1416 women free of probable dementia who were randomized to CEE+MPA or placebo and followed for a 1.35 yr prior to the early termination of the main WHI trial due to an increase in risk for breast cancer in HT-treated women and an adverse risk-benefit profile. Analysis of annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, showed that CEE + MPA had a negative impact on verbal memory (p <0.01) and a trend to a positive impact on figural memory (p = 0.012) over time compared with placebo with no effect on other cognitive domains. In addition, these effects were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms. These findings suggest that HT may have different effects across different cognitive domains. The results of the CEE-Alone Trial in women with prior hysterectomy who were randomized to CEE or placebo are currently in press in Journal of Clinical Endocrinology and Metabolism. More recently, through the related WHIMS-MRI study, we have reported with our WHIMS collaborators that HT was associated with decreased hippocampal and frontal regional brain volumes in more than 1400 women evaluated post-trial with brain MRI scans. This adverse effect of HT on hippocampal volume was most pronounced in women who had the lowest scores on a measure of global cognitive function at WHI baseline.